Modern cancer therapy relies strongly on the use of ionizing irradiation, either alone or in combination with surgery or chemotherapy, as a primary strategy for the treatment of malignancies of various types. Ionizing radiation induces multiple and varying biochemical events in various cell types determining the ability of the cell to survive the radiation challenge. As a result, different normal and malignant tissues in the body display variable radio-sensitivity. For example, radiotherapy to the gastro-intestinal (GI) tract can cause a potentially fatal GI syndrome, nephrotoxicity, esophagitis and lung complications. After irradiation, cells can be lost due to apoptosis, or through interference with cellular repair mechanisms or subsequent cell division leading to eventual cell death. A recent study on gastrointestinal tract irradiation damage in mice proposed that endothelial cell apoptosis is the primary lesion of irradiation induced damage followed by epithelial damage. Side effects of radiotherapy relate to the damage caused to normal surrounding tissues while irradiating the target tumor.
Each year, newly diagnosed cases of oral and laryngeal cancer are reported for more than 41,000 Americans and between 350,000-400,000 world wide. Irradiation-induced xerostomia, or dry mouth, is a direct consequence of the high sensitivity of the salivary glands to ionizing radiation, and is the most common toxicity associated with standard fractionated radiation therapy to patients suffering from cancers of the head and neck.
Radiation produces changes in the salivary gland secretory cells, resulting in a reduction in salivary output and increased viscosity of the saliva. Xerostomia varies from scant to complete and is potentially debilitating. Acute radiation-induced xerostomia is associated with an inflammatory response, while late xerostomia, which can occur up to one year after radiation therapy, results in fibrosis of the salivary glands and is usually permanent. Both the parotid and submandibular glands show similar morphologic alterations after irradiation, but the exact mechanism mediating radiation induced cell death is not yet known. A correlation between the radiation induced salivary gland damage and the role of intracellular redox-active metal ions has been reported. One hypothesis explaining the mechanism for the salivary gland radio-sensitivity suggests that radiation causes the disruption of salivary gland granules, the contents of which leak into the cytoplasm causing redistribution in the cell of loosely bound metal ions, including iron and copper that reach the DNA and promote damage by generation of free radicals and reactive oxygen species (ROS). Other factors such as the enhanced production of p53 and calcium overload are also thought to be involved. Unlike the changes in the GI tract, chronic acinar atrophy seen in the parotid is considered to be a consequence of direct, irreversible, and early injury, not the result of radiation-induced changes in the vasculature.
The most important factors that determine the severity of salivary gland damage from therapeutic irradiation in patients are the dose of radiation delivered and the volume of gland exposed to the radiation. When the total radiation dose exceeds 52 Gy, salivary flow is reduced or even totally inhibited so that no saliva is secreted from the salivary glands to the mouth. These changes are usually permanent. As a result, patients suffer from acute effects and face residual impairments. Late effects include nutritional problems due to difficulty in chewing, swallowing and tasting, and communication problems due to severe difficulties of speech. Severe ulcers and infections develop in the oral mucosa due to the impairment of the oral immune system, aggravating the patient's state of health. In a recent survey on quality of patient life issues, 10-24% of irradiated head and neck cancer patients placed high importance on the oral side effects of their treatment.
U.S. Pat. No. 5,994,409 to Stogniew et al. discloses methods for treating toxicities associated with the exposure of a human to antineoplastic radiation therapy which comprises administering to said human of an aminothiol compound, preferably amifostine. U.S. Pat. No. 5,994,409 further discloses methods for treating xerostomia induced in a human by antineoplastic chemotherapy or antineoplastic radiation therapy comprising administering to said human an aminothiol compound, preferably amifostine.
While amifostine has been shown to be useful as a radiation protectant in cancer patients receiving radiation therapy, it has also been reported that intravenous administration of amifostine suffers from undesirable side effects such as nausea, vomiting, emesis, hypotension, flushing, chills, dizziness and sneezing. In order to reduce the side effects associated with intravenous administration of amifostine, U.S. Pat. No. 6,573,253 to Stogniew et al. discloses methods for protecting against or treating the toxicities associated with ionizing radiation in a subject comprising subcutaneously administering to the subject an aminothiol compound. Among the toxicities disclosed is xerostomia.
International Patent Application Publication No. WO 2005/113591 of Mackiewicz et al. discloses uses of H11, a complex polypeptide consisting of soluble interleukin-11 receptor (sIL-11R) and IL-11, in treating or preventing a proliferative disease, a cytopathy, and radiation damage, though no specific enablement or guidance is provided for treating or preventing radiation damage.
The cytokine interleukin-6 (IL-6) was shown to exert radio-protective activity only when administered with IL-1 and TNF to mice exposed to total-body irradiation (Neta et al., J. Exp. Med. 175: 689-694, 1992; Legue et al., Cytokine 16: 232-238, 2001). However, when IL-6 was administered by itself to mice exposed to total-body irradiation, it was ineffective as a radio-protectant (Neta et al., ibid.). It has been hypothesized that IL-6 contributes to the adaptive response to oxidative stress generated by gamma-irradiation (Brouazin et al., Anticancer Res. 22: 257-262, 2002).
IL-6 is a member of a family of cytokines that act via receptor complexes containing at least one subunit of the transmembrane signal transducing protein, gp130, which is found in almost all organs, including heart, kidney, spleen, liver, lung and brain. On target cells, IL-6 acts by binding to a specific transmembrane cognate receptor (gp80 or IL-6Rα), hereafter IL-6R, which triggers the homodimerization of gp130 (also called IL-6Rβ) and leads to the activation of the Jak/Stat signaling pathway, particularly of STAT-3. Unlike gp130, the endogenous expression of gp80 is naturally found in relatively few tissues in the body, including liver, intestine, and some B cells and T cells. Thus, because of the lack of the gp80 expression, only a few cell populations in the body would be expected to respond to IL-6 stimulation. However, in addition to its membrane bound form, the IL-6R is also found in a soluble form (sIL-6R), which when complexed with IL-6, is capable of stimulating cells via interaction with gp130. Importantly then, in a process called IL-6 trans-signaling, IL-6/sIL-6R complexes are capable of acting as an agonist on cell types that, although they express gp130, would not inherently respond to IL-6 alone.
A recombinant fusion protein called Hyper-IL-6 consisting of the human IL-6 linked by a flexible peptide chain to sIL-6R was shown to be a super agonistic designer cytokine (Fischer, M., et al. Nat. Biotechnol. 15: 142-145, 1997). Hyper-IL-6 is fully active on gp130-expressing cells at concentrations 100 to 1000 fold lower than the combination of unlinked IL-6 and sIL-6R, and exhibits a super agonistic effect both in vitro and in vivo, due to the 100 times higher affinity of the IL-6/sIL-6R complex to gp130 and due to its prolonged half-life in vivo (Peters, M., et al. J. Immunol. 161: 3575-3581, 1998).
U.S. Pat. No. 5,919,763 to Galun et al. discloses methods for treating an injury to a liver of a subject comprising administering to the subject a pharmaceutical composition comprising an IL-6/sIL-6R complex, preferably Hyper-IL-6.
International Application Publication No. WO 99/62534 to Galun et al. discloses methods for treating an injury to a liver of a subject comprising administering to the subject a pharmaceutical composition comprising an IL-6/sIL-6R complex, preferably Hyper-IL-6. WO 99/62534 further discloses methods of gene therapy for treating an injury to a liver of a subject comprising administering to the subject a vector carrying Hyper-IL-6 chimera gene.
International Application Publication No. WO 03/029281 to Axelrod et al. discloses a therapeutic composition comprising an IL-6 family member, preferably an IL-6/sIL-6 complex, and a liver regenerating factor. WO 03/029281 further discloses methods for treating a pathological condition in a subject comprising administering to the subject a therapeutic composition comprising an IL-6 family combination component and a liver regenerating factor, wherein at least one of the IL-6 family combination component and the liver regenerating factor is administered encoded by a plasmid.
International Application Publication No. WO 2006/134601 to Axelrod et al. discloses methods for preventing or treating renal failure comprising administering to a subject a pharmaceutical composition comprising a complex which comprises a member of the IL-6 family linked to a soluble receptor of the member of the IL-6 family. Preferably, the member of IL-6 family linked to a soluble receptor of the member of the IL-6 family is an IL-6/sIL-6 complex.
Nowhere in the background art is it disclosed or suggested that IL-6/sIL-6 receptor complexes are useful for protecting against or treating toxicities associated with ionizing radiation and chemotherapy.